THE INVESTIGATION OF PHOTOCHEMICAL REACTIONS OF PHOTOTOXIC ANTIMALARIAL COMPOUNDS

YOON UNG CHAN, Fordham University

Abstract

The goal of this research is to provide information that will lead to the development of new non-phototoxic anitmalarial compounds. The goal^was approached by first learning the chemical mechanism of phototoxicity of six representative compounds 1a-f; (alpha)-{(diethyl-, -dihexyl-, and^ -dioctyl-aminomethyl)}-2-(3',4'-dichlorophenyl)-6-methoxy-4-quinolinemethanol (1a, 1b, and 1c) and (alpha)-{(diethyl-, -dibutyl-, and -dihexyl-aminomethyl)}-2-(4'-methoxyphenyl)-6-methoxy-7-chloro-^4-quinolinemethanol (1d, 1e, and 1f). The photochemical reaction of^ these compounds was investigated in 2-propanol. Similar photochemical fragmentation reactions occurred in all compounds. Five products (15-19), formed via cleavage of the whole side chain (bond "a" cleavage) and^ cleavage of bond between (alpha)-carbon and hydroxy carbon (bond "b" cleavage), were isolated and identified; 2-(3',4'-dichlorophenyl)-6-^methoxyquinoline (15), 2-(3',4'-dichlorophenyl)-4-hydroxymethyl-6-^methoxyquinoline (16), 2-(3',4'-dichlorophenyl)-6-methoxyquinoline-^ 4-carboxaldehyde (17), 2-(3',4'-dichlorophenyl)-4-((alpha),(beta)-dihydroxy-(beta)-^methyl-propyl)-6-methoxyquinoline (18), and the pinacol-type of dimer^of 16 (19). A radical mechanism was proposed for the formation of 15-19. Quantum yields of the photochemical reaction of 1a-f were measured to determine if the efficiency of the reaction parallels the degree of phototoxicity of 1a-f. A good qualitative correlation was observed.^ Fluorescence study of 1a-d, 2-(3',4'-dichlorophenyl)-4-ethyl-6-methoxyquinoline, 2-(3',4'-dichlorophenyl)-4-((alpha)-hydroxyethyl)-6-methoxyquinoline, and 2-(4'-methoxyphenyl)-4-((alpha)-hydroxyethyl)-^ 6-methoxy-7-chloroquinoline was performed to investigate whether intramolecular exciplex formation between an aliphatic amine group and quinoline ring could intervene in the photochemistry of 2-arylquinolinemethanols. Significant intramolecular fluorescence quenching by the aliphatic amine group of 1a-d was noticed.^ Sensitization irradiations of 1a with triplet sensitizers failed to produce 16-19, producing only 15 in low yield. The reaction of 1a-f was partially quenched by oxygen. The singlet excited state and an intramolecular exciplex of 2-arylquinolinemethanols were postulated to be reactive states for their photochemical reactions.^ Photochemical reactions of cinchonidine (33a), quinine (33b),^cinchonine (33c), quinidine (33d), and mefloquine (50) were investigated.^5-Vinylquinuclidine-2-carboxaldehyde (34) was isolated and identified^ as a major product in the reaction of 33a-d. The formation of 34 was rationalized by a charge transfer mechanism. Bond "b" cleavage was blocked by the bicyclic amine group, quinuclidine of 33a-d. A different photochemical reaction was observed in the photolysis of 50 from those of 1a-f and 33a-d, and 2,8-bis(trifluoromethyl)-4-carbomethoxyquinoline was isolated as the major photoproduct in methanol.^ Finally, structural changes to increase charge transfer character in the intramolecular exciplex and to increase the efficiency of intersystem crossing were suggested as ways to stop or diminish the phototoxicity of 2-arylquinolinemethanols. ^

Subject Area

Organic chemistry

Recommended Citation

YOON UNG CHAN, "THE INVESTIGATION OF PHOTOCHEMICAL REACTIONS OF PHOTOTOXIC ANTIMALARIAL COMPOUNDS" (1981). ETD Collection for Fordham University. AAI8111323.
https://fordham.bepress.com/dissertations/AAI8111323

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